Paternal HBV Infection Linked to Higher Risk of Congenital Heart Defect in Offspring

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Paternal hepatitis B virus (HBV) infection prior to conception may be linked to congenital heart disease risk in offspring, according to findings from a recent study published in JAMA Pediatrics.¹

Leveraging data from couples who planned for pregnancy through participation in the Chinese National Free Preconception Checkup Project (NFPCP), the study found previous, but not new, preconception HBV infection among male participants was associated with a greater risk of congenital heart diseases in their children.¹

“To our knowledge, limited evidence existed before the present study in terms of the association between paternal preconception HBV infection and risk of congenital heart diseases in offspring,” Ying Yang, PhD, an associate professor at the National Research Institute for Family Planning in China, and colleagues wrote.¹

According to the US Centers for Disease Control and Prevention, congenital heart defects affect nearly 1% of births, or about 40,000 babies, each year. Although the exact cause is unknown, certain maternal conditions, smoking during pregnancy, and certain medications taken during pregnancy are recognized as risk factors.² Maternal HBV infection has also been found to influence the risk of their children having a congenital heart defect, but knowledge about such an association with paternal HBV infection is limited.¹

To explore the association between paternal preconception HBV infection and congenital heart diseases in offspring, investigators conducted a retrospective cohort study of NFPCP participants from January 1, 2010, to December 31, 2018. Located in mainland China, the service provides free prepregnancy health examinations, counseling services, and follow-up of pregnancy outcomes to couples planning for pregnancy.¹

Male participants whose partners were 20-49 years of age, were uninfected with HBV, and successfully conceived within 1 year after prepregnancy examination were enrolled in the present study. Couples were sequentially excluded if data were missing on the female participants’ hepatitis B serologic markers, the female participants had previous or new HBV infection, or data were missing on the male participants’ hepatitis B serologic markers.¹

The primary exposure was paternal preconception HBV infection status, classified into 3 groups based upon hepatitis B serologic markers: uninfected, previous infection (both serum HBsAg and HBeAg negative), or new infection (serum HBsAg positive). Uninfected participants were either susceptible (all serum markers negative) or immune due to prior vaccination (serum HBsAg negative, serum HBcAb negative, serum HBeAg negative, serum HBeAb negative, and serum HBsAb positive).¹

The primary outcome was congenital heart disease recorded on the birth defect registration card of the NFPCP. These included atrial septal defect, ventricular septal defect, atrioventricular septal defect, tetralogy of Fallot, pulmonary stenosis, and transposition of the great arteries.¹

Investigators performed propensity score matching (PSM) using a nearest-neighbor matching algorithm among included males. The HBV-infected male participants and uninfected male participants were matched in a 1:4 ratio.¹

Of 6,675,540 eligible couples who participated in the NFPCP service, 3,047,924 were matched and thus included in the analysis. Among the matched male participants, the median age was 27 (Interquartile range [IQR], 25-30) years and 38.4% were previously infected with HBV.¹

Among the cohort, 0.025% of couples had children with congenital heart diseases. By HBV infection status, the prevalence rate was 0.023% among uninfected fathers, 0.036% among fathers with previous HBV infection, and 0.028% among fathers with new HBV infection.¹

Upon analysis, previous paternal HBV infection was independently associated with congenital heart diseases in offspring (adjusted relative risk [aRR], 1.40; 95% CI, 1.11-1.76) compared with no infection, but there was no association between new paternal HBV infection and risk of congenital heart diseases (aRR, 1.10; 95% CI, 0.89-1.36). Compared with couples with HBV-uninfected fathers and HBV-susceptible mothers, investigators noted the risk of congenital heart diseases in offspring was greater for couples with previously HBV-infected husbands, regardless of maternal immune status (wives with HBV susceptibility: aRR, 1.49; 95% CI, 1.10-2.03 vs wives with HBV immunity: aRR, 1.49; 95% CI, 1.07-2.09).¹

Further analysis revealed a significantly increased congenital heart disease risk in offspring among couples with newly infected fathers and immune mothers (aRR, 1.38; 95% CI, 1.05-1.82), but there was no difference in risk among those with newly infected husbands and susceptible wives (aRR, 0.99; 95% CI, 0.72-1.36). Investigators noted there was no interaction between maternal HBV immune status and paternal HBV infection prior to pregnancy.¹

Investigators outlined multiple limitations to these findings, including their inability to assess the association of different paternal HBV DNA loads with the risk of congenital heart diseases in offspring; the lack of consideration of medical records for patients with new HBV status potentially receiving treatment and monitoring at a hospital; the fact they did not account for additional variables potentially affecting the association between paternal HBV infection and congenital heart disease in offspring; and the lack of documentation of the specific subtypes of congenital heart disease.¹

“These findings provide important evidence for studying paternal HBV infection as a factor associated with congenital heart diseases in offspring,” investigators concluded.¹ “The findings suggest that personalized reproductive guidance regarding undergoing HBV screening and staying free of HBV infection should be provided for both wives and husbands, which might be helpful for the reduction of congenital malformation risk and improvement of neonatal outcomes.”

References

1. ^{Yang Y, Liu M, Han J, et al. Paternal Preconception Hepatitis B Virus Infection and Risk of Congenital Heart Disease in Offspring. JAMA Pediatr. doi:10.1001/jamapediatrics.2024.2680}
2. ^{US Centers for Disease Control and Prevention. Congenital Heart Defects. About Congenital Heart Defects. August 19, 2024. https://www.cdc.gov/heart-defects/about/index.html}